Inflammatory myofibroblastic tumor.
Inflammatory myofibroblastic tumor (IMT) is a histologically distinctive lesion that occurs primarily in the viscera and soft tissue of children and young adults, and usually pursues a benign clinical course (3). Although original descriptions of this entity were mostly in the lung, IMT has been described in virtually every anatomic location. In the past, IMT has been classified under many designations, including plasma cell granuloma, plasma cell pseudotumor, inflammatory myofibrohistiocytic proliferation, omental-mesenteric myxoid hamartoma and, most commonly, inflammatory pseudotumor. In the 2002 World Health Organization classification of soft tissue tumors, this heterogeneous group of lesions were renamed "IMTs" (10). The most common sites of extrapulmonary IMT are the mesentery and omentum. Although the age range is broad, extrapulmonary IMT show a predilection for children, with a mean age of approximately 10 years. Females are slightly more commonly affected than males. In the central nervous system (IMT-CNS), the diagnosis is controversial, because of the high frequency of recurrence and malignant transformation (4,5). The etiology of IMT remains unknown. IMT was initially thought to represent a purely inflammatory lesion, but subsequent evidence underscores the potential for recurrence, infiltrative local growth, and even malignant transformation (3).
Presenting symptoms depend on the site of primary tumor involvement. Some patients have prominent systemic manifestations, including fever, night sweats, weight loss and malaise. Laboratory abnormalities are present in a small number of patients and include an elevated erythrocyte sedimentation rate, anaemia, thrombocytosis, and hypergammaglobulinemia, which often resolve when the lesion is excised (8).
Histopathologically, IMT is essentially a diagnosis of exclusion. The differential diagnosis includes mainly low-grade myofibroblastic sarcoma (LGMS) and other benign or malignant spindle-cell tumors such as leiomyoma, solitary fibrous tumor, spindle-cell carcinoma, nodular fasciitis, desmoids, infantile myofibromatosis, and peripheral nerve-sheath tumor (6). Due to similar morphological and immunophenotypic features, distinguishing IMT from LGMS may be challenging. A subset of IMT stains positively for ALK-1 and cytokeratin, whereas LGMS is usually negative (6). Moreover, studies of ALK-1 in nodular fasciitis, desmoids and infantile myofibromatosis suggest that ALK-1 is specific for IMT within the spectrum of myofibroblastic tumors (6,9).
A variety of histologic patterns are recognized, sometimes even in the same tumor. Some tumors are composed predominantly of cytologically bland spindle- or stellate-shaped cells loosely arranged in a myxoid or hyaline stroma with scattered inflammatory cells, somewhat resembling nodular fasciitis. Other tumors are composed of a compact proliferation of spindle-shaped cells arranged in a storiform or fascicular growth pattern. Mitotic figures are variable. These foci are usually associated with prominent lymphoplasmacytic infiltrates, occasionally with the formation of germinal centers. Other foci may be sparsely cellular, with cytologically bland cells deposited in a sclerotic stroma resembling a scar. In some lesions, there is pronounced cytological atypia, with cells containing large nuclei and distinct nucleoli, which resemble ganglion cells (8).
Tumor cells stain strongly for calponin (100%), fibronectin (100%), and variably with myoid markers, including smooth muscle actin (95.8%), muscle-specific actin (100%), desmin (33.3%) and laminin (81.8%) (9). Focal cytokeratin (13.6%) can be seen; however, CD34 and S-100 protein are negative in all cases. As noted, some IMTs stain for ALK-1 (40.9%). Remarkably, the average patient age for ALK-1-positive cases was 14.8 years, whereas the average age for ALK-negative cases was 37.9 years (9).
Rearrangement of the ALK-1 locus on chromosome 2p23, which codes for a tyrosine kinase receptor member of the insulin growth factor receptor superfamily, has been documented in approximately 50% of cases and implicated in the pathogenesis of IMT. ALK-1 rearrangements result in constitutive expression and activation of this gene with abnormal phosphorylation of cellular substrates (1). Of note, the majority of ALK-1 negative cases are associated with EBV, whereas in our case, the tumor lacked both ALK-1 rearrangement and was EBV negative.
The therapeutic approach for IMT encompasses surgery, steroid therapy, radio- and chemotherapy (6). Notably, a sustained partial response to the ALK-1 inhibitor crizotinib (PF-02341066, Pfizer) has been described in a single patient with ALK-1-translocated IMT (1). In a recent retrospective study, the presence of positive surgical margins was the most significant independent predictor for local relapse. The progression-free-survival for 2 and 5 years was 72% and 65%, respectively. Gender, patient age and delayed diagnosis did not significantly affect the likelihood of recurrence or overall survival. Additionally, for every 1-cm-increase in diameter, the risk of relapse was increased by 60% and the risk of death was increased by 55%. However, mitotic count and nuclear atypia were not found to be prognostically significant (7).
Contributed by Alejandra Magagna-Poveda, MD, PhD; Karl J. Frontzek, MD; Beata Bode-Lesniewska, MD; Elisabeth J. Rushing, MD